# Exploration and Characterization of the Antimalarial Activity of Pyrimidine‐2,4‐Diamines for which Resistance is Mediated by the ABCI3 Transporter

## TL;DR

This study explores new antimalarial compounds that work against drug-resistant malaria parasites by targeting a specific transporter protein.

## Contribution

The study identifies pyrimidine-2,4-diamines as a new class of antimalarials and links resistance to the ABCI3 transporter.

## Key findings

- Pyrimidine-2,4-diamines show potent antimalarial activity, with analog 51 being the most effective.
- Resistance to these compounds is mediated by the ABCI3 transporter protein.
- The compounds arrest parasite development at the ring to trophozoite transition stage.

## Abstract

The spread of drug‐resistant Plasmodium strains is diminishing the effectiveness of current antimalarials, highlighting the importance of discovering new therapeutics with novel targets. A screen of the Jumpstarter library against P. falciparum identified W482 with a pyrimidine‐2,4‐diamine scaffold. Structure‐activity relationships reveal the importance of the pyrimidine core and its endocyclic nitrogen, while alternative amines are tolerated in the 4‐position. Bulky and hydrophobic carboxamides or substituted phenyl ureas display the most potent antiplasmodial activity. Resistance selection and whole genome sequencing reveal an amplification of the gene encoding the ABCI3 transporter protein W482‐resistant parasites. W482 is found to exhibit greater activity against parasites with reduced expression of ABCI3, confirming that resistance is related to the transporter. W482 arrests asexual parasites at the ring to trophozoite transition stage and exhibits a fast‐killing profile with a lag phase of 24 h. Improving the antiparasitic activity alongside metabolic stability and solubility remains a challenge in the future development of the pyrimidine‐2,4‐diamine class.

Investigation of the structure‐activity relationship on W482 (1) with a pyrimidine‐2,4‐diamine scaffold culminated in analog 51 with enhanced anti‐plasmodial activity. Forward genetics and phenotypic examination revealed the ABCI3 transporter protein as a putative resistance mechanism. Enhancing physicochemistry and potency are challenges for the future development of this class.© 2026 WILEY‐VCH GmbH